Chikungunya virus (CHIKV) is an emerging mosquito-transmitted alphavirus that causes an abrupt onset of fever with severe joint and muscle pain. In a significant number of patients chronic and debilitating arthritis can persists for months to years, with recent epidemiological projections suggesting there are 400,000 patients in the Western Hemisphere with chronic CHIKV arthritis. The pathogenesis of CHIKV arthritis is poorly understood. Evidence from humans, non-human primates, and mouse studies suggest that CHIKV replicates within the joint tissue and muscle cells and that persistent viral RNA can be detected long after acute infection is cleared. However, due to technical limitations, the cells harboring this viral RNA have not been identified and how they contribute to disease is unclear. In preliminary data we have engineered a recombinant CHIKV virus to express Cre recombinase and we have shown that this virus establishes chronic infection, including persistent RNA. When this virus was used to infect tdTomato reporter mice we found marked cells that persisted even after replicating virus has been cleared. In this proposal we will use this novel system to begin to ask several questions including: 1) which cell types are infected by CHIKV and which ones harbor persistent viral RNA?; 2) what is the sequence of the RNA that persists and why does it not result in productive replication?; 3) are the cell types that survive CHIKV infection transcriptionally altered?; and 4) do the cells that survive CHIKV infection contribute to disease pathogenesis? Overall, our studies will provide important insight into the pathogenesis of chronic CHIKV arthritis and may direct efforts toward the development of future therapeutics.